PROJECT SUMMARY The damage or degeneration of the axons derived from the retinal ganglion cells (RGCs) in the optic nerve accounts for the visual functional defects after traumatic injury or degenerative diseases such as glaucoma. Thus, the logical repair strategy is to promote injured optic nerve axons to regenerate across the lesion and reconnect with their targets. In the previous funding period, we have made significant progress in optimizing regeneration-promoting strategies. We first discovered that co-deletion of PTEN and SOCS3 resulted in robust axon regeneration. Our further studies showed that over-expression of osteopontin (OPN) and IGF1 and CNTF could mimic the effects of co-deletion of PTEN and SOSC3, leading to similar extents of axon regeneration. However, such regenerated axons fail to re-myelinate preventing recovery of vision unless potassium channel blocker is acutely administered to allow axonal conduction of neuronal signal. Since OPN/IGF1/CNTF are all extracellular proteins and recombinant proteins can be produced, this combination may be the most promising treatment for stimulating RGC axon regeneration and vision function recovery. To further develop this into an effective therapeutic strategy, we need to address the following issues: can OPN/IGF1/CNTF combination stimulate all types of RGCs to regenerate axons? Do regenerated axons project to correct targets? How can re-myelination be induced? Using the optic nerve and optic tract regenerative animal model, we will address each of these questions, in a hope to reveal key cellular and molecular regulators these processes. We expect that the obtained results might provide insights into develop more effective and safe therapeutic strategies of promoting vision restoration.